Treatment of Vitamin D Insufficiency

The purpose of this study is to answer the following questions: Does vitamin D increase calcium absorption, bone mass and muscle mass and function in women past menopause who have mildly low vitamin D levels? Do these benefits require prescription-strength vitamin D, or is an over the counter vitamin D dose enough?

Study Overview

• Status: Completed
• Conditions: Vitamin D Deficiency
• Intervention / Treatment: Dietary supplement: High Dose Vitamin D3; Dietary supplement: Low Dose Vitamin D3; Dietary supplement: Placebo

Detailed Description

Osteoporosis is a major health problem in postmenopausal women. At age 50, half of women will suffer an osteoporotic fracture in their remaining lifetime, causing increased disability and mortality. Vitamin D deficiency, defined as a serum 25(OH)D <15 ng/mL, contributes to osteoporosis via decreased calcium absorption (Ca·Ab), secondary hyperparathyroidism (HPT), increased bone resorption and decreased bone mineral density (BMD). Thus, experts agree that patients with vitamin D deficiency should receive vitamin D therapy.

Vitamin D insufficiency (VDI) is a milder form of hypovitaminosis D defined as a 25(OH)D level between 15 and 30 ng/mL regardless of parathyroid hormone (PTH) status. Experts disagree on whether to treat VDI, as the clinical benefits of therapy are uncertain. Some experts insist the optimal 25(OH)D level is ≥30 ng/mL. By contrast, both the Food and Nutrition Board and NIH Evidence Report No. 158 state that insufficient evidence exists to declare the optimal serum 25(OH)D for bone health, despite review of ~170 studies. Consequently, the Food and Nutrition Board cannot determine a recommended daily allowance for vitamin D. Confusion over the optimal 25(OH)D level results, in part, because previous trials failed to recruit subjects based on initial 25(OH)D levels and/or failed to target or achieve 25(OH)D levels ≥30 ng/mL. Moreover, secondary HPT, the proposed mechanism by which VDI causes bone loss, occurs in only 10% to 33% of people with VDI. As such, people with VDI and normal PTH might not experience clinical benefits from vitamin D therapy. VDI is widespread, affecting 26% to 39% of postmenopausal American women with and without osteoporosis. Therefore, determining the ideal 25(OH)D level for optimal calcium homeostasis and bone health is of utmost clinical and public health importance. Our overall goal, congruent with Healthy People 2010 objective 2-9, is to evaluate the effect of vitamin D therapy on the risk of osteoporosis in postmenopausal women with VDI, as reflected by changes in Ca·Ab, BMD and muscle fitness. Our second goal is to evaluate whether a high-dose vitamin D regimen, chosen to achieve and maintain a 25(OH)D level ≥30 ng/mL, is superior in its effects on study outcomes compared to a low-dose vitamin D regimen that can permit continued VDI.

We will conduct a randomized, placebo-controlled double-blind trial of low-dose and high-dose vitamin D in postmenopausal women with vitamin D insufficiency in order to investigate the following aims:

1. To evaluate the effect of vitamin D3 therapy on Ca·Ab in postmenopausal women less than or equal to 75 years old with VDI. Sub-aims include the investigation of subject variables influencing Ca·Ab and 25(OH)D levels at baseline and one month, the accuracy of oral isotope plasma levels for Ca·Ab measurement and the ability of a questionnaire to identify patients with low vitamin D status.
2. To evaluate the effects of vitamin D3 therapy on the 12-month change in BMD and bone turnover in the same trial conducted for Aim 1. Sub-aims include the identification of subject variables significantly influencing change in BMD and an evaluation of the relationship between changes in Ca·Ab and changes in BMD.
3. To evaluate the effect of vitamin D therapy on muscle mass and functional capacity in the same trial conducted for Aim 1. We will measure muscle mass by whole body bone densitometry and assess muscle function using the Timed Up and Go (TUG) Test and the modified Stanford Health Assessment Questionnaire (HAQ) score. Sub-aims include the identification of subject variables significantly influencing muscle outcomes.

• Study Type: Interventional
• Enrollment (Actual): 230
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin School of Medicine and Public Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Vitamin D insufficiency, defined as a serum 25(OH)D 16 to 25 ng/mL by high performance liquid chromotography assay
• Women ≥ 5 years past the date of last menses or bilateral oophorectomy, or ≥ 60 years old if they had prior hysterectomy without bilateral oophorectomy
• Total dietary and supplemental calcium intake < 600 mg daily but ≤ 1,400 mg daily, based on a food frequency questionnaire

Exclusion Criteria:

• Women > 75 years old
• Hypercalcemia (serum calcium corrected for albumin > 10.4 mg/dL)
• Nephrolithiasis by medical record or patient report
• Inflammatory bowel disease, malabsorption or chronic diarrhea
• Stage 3, 4 or 5 Chronic Kidney Disease based on the Modification of Renal Diet (MDRD) formula
• Use of bone-active medications within the past 6 months including bisphosphonates, estrogen compounds, calcitonin, teriparatide, oral corticosteroids and anticonvulsants
• Allergy or intolerance to orange juice
• Allergy or intolerance to sunscreen
• Prior adult clinical fragility fracture of the hip, spine or wrist or a T-score below -2.5 at the lumbar spine or femur

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: High Dose Vitamin D3; Loading Dose: 50,000 International Units vitamin D3 gel-caps (yellow) to take daily for 15 days and placebo gel-caps (white) to take daily for 15 days. Maintenance Dose: 50,000 International Units vitamin D3 gel-caps (yellow) to take two times a month for 350 days and placebo gel-caps (white) to take daily for 350 days.	Dietary supplement: High Dose Vitamin D3; Yellow gel-cap vitamin D3 at 50,000 International Units daily for 15 days then two times a month for 350 days. Daily white placebo pills.; Other Names: Cholecalciferol; Vitamin D
Other: Low Dose Vitamin D3; Loading Dose: 800 International Units vitamin D3 gel-caps (white) to take daily for 15 days plus placebo gel-caps (yellow) to take daily for 15 days. Maintenance Dose: 800 International Units vitamin D3 gel-caps (white) to take daily for 350 days plus placebo gel-caps (yellow) to take two times a month for 350 days.	Dietary supplement: Low Dose Vitamin D3; White gel-cap vitamin D3 at 800 International Units to take orally, daily for 365 days. Intermittent yellow placebo pills.; Other Names: Cholecalciferol; Vitamin D
Placebo Comparator: Placebo; Loading Dose: Placebo gel-caps (yellow) to take daily for 15 days plus placebo gel-caps (white) to take daily for 15 days. Maintenance Dose: Placebo gel-caps (yellow) to take two times a month for 350 days plus placebo gel-caps (white) to take daily for 350 days.	Dietary supplement: Placebo; Yellow gel-cap placebo pills to take orally, daily for 15 days then two times a month for 350 days. White gel-cap placebo pills once daily for 365 days.; Other Names: sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intestinal Calcium Absorption	Percent of calcium absorbed in the intestinal tract within one day	One Year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone Mineral Density	Annualized percent change in bone mineral density at spine, hip, femoral neck, and body	1 Year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone Turnover	C-telopeptide (pg/mL) was measured at baseline, 30 days, 60 days, 120 days, 365 days in the subset of subjects who arrived at all study visit fasting since midnight and had phlebotomy prior to 10 am. Data demonstrated outliers and was summarized using the median (25th, 75th interquartile range).	0, 30, 60, 120, 365 days
Muscle Function: One Year Change in Timed Up and Go Test, Five Sit-to-Stand Test	We summarized within-arm one-year changes in continuous muscle outcomes using the mean (95% confidence interval).	1 Year

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: National Institutes of Health (NIH); National Institute on Aging (NIA)
• Investigators: Principal Investigator: Karen E Hansen, MD, MS, University of Wisconsin, Madison

Publications and helpful links

General Publications

• Hansen KE, Jones AN, Lindstrom MJ, Davis LA, Engelke JA, Shafer MM. Vitamin D insufficiency: disease or no disease? J Bone Miner Res. 2008 Jul;23(7):1052-60. doi: 10.1359/jbmr.080230.
• Ramsubeik K, Keuler NS, Davis LA, Hansen KE. Factors associated with calcium absorption in postmenopausal women: a post hoc analysis of dual-isotope studies. J Acad Nutr Diet. 2014 May;114(5):761-7. doi: 10.1016/j.jand.2013.07.041. Epub 2013 Oct 24.
• Nabak AC, Johnson RE, Keuler NS, Hansen KE. Can a questionnaire predict vitamin D status in postmenopausal women? Public Health Nutr. 2014 Apr;17(4):739-46. doi: 10.1017/S1368980013001973. Epub 2013 Jul 22.
• Hansen KE, Johnson RE, Chambers KR, Johnson MG, Lemon CC, Vo TN, Marvdashti S. Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial. JAMA Intern Med. 2015 Oct;175(10):1612-21. doi: 10.1001/jamainternmed.2015.3874.
• Vreede AP, Jones AN, Hansen KE. Can serum isotope levels accurately measure intestinal calcium absorption compared to gold-standard methods? Nutr J. 2015 Jul 31;14:73. doi: 10.1186/s12937-015-0065-5.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: July 2, 2009
• First Submitted That Met QC Criteria: July 6, 2009
• First Posted (Estimate): July 7, 2009

Study Record Updates

• Last Update Posted (Estimate): November 10, 2015
• Last Update Submitted That Met QC Criteria: October 6, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Vitamin D; Cholecalciferol; Parathyroid Hormone; Bone Mineral Density; Muscle Function; Calcium Absorption
• Additional Relevant MeSH Terms: Nutrition Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Vitamin D Deficiency; Physiological Effects of Drugs; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols
• Other Study ID Numbers: H-2009-0055; supplement (Other Identifier: Office of Dietary Supplements); R01AG028739 (U.S. NIH Grant/Contract)